Relaxation of rabbit corpus cavernosum smooth muscle and aortic vascular endothelium induced by new nitric oxide donor substances of the nitrosyl-ruthenium complex

Abstract

Introduction: Endothelial dysfunction characterized by endogenous nitric oxide (NO) deficiency made 56% of patients affected with erectile dysfunction decline treatment with PDE-5 inhibitors. New forms of treatment are currently being developed for this group of patients. Materials and Methods:The study compared the effect of sodium nitroprusside (SNP) and two substances of the nitrosylruthenium complex, cis-[Ru(bpy)2(SO 3 )(NO)]PF-6-9 ("FONO1") and trans-[Ru(NH 3 )4(caffeine)(NO)]C13 ("LLNO1") on relaxation of rabbit corpus cavernosum smooth muscle and aortic vascular endothelium. The samples were immersed in isolated baths and precontracted with 0.1 µM phenylephrine (PE) and the corresponding relaxation concentration/response curves were plotted. In order to investigate the relaxation mechanisms involved, 100 µM ODQ (a soluble guanylate cyclase-specific inhibitor), 3 µM or 10 µM oxyhemoglobin (an extracellular NO scavenger) or 1 mM L-cysteine (a nitrosyl anion-specific scavenger) was added to the samples. Results: All the NO donors tested produced a significant level of relaxation in the vascular endothelium. In corpus cavernosum samples, FONO1 produced no significant effect, but LLNO1 and SNP induced dose-dependent relaxation with comparable potency (pEC 50 = 6.14 ± 0.08 and 6.4 ± 0.14, respectively) and maximum effect (Emax = 82% vs. 100%, respectively). All NO donors were found to activate soluble guanylate cyclase, since the addition of the corresponding inhibitor (100 µM ODQ) completely neutralized the relaxation effect observed. The addition of oxyhemoglobin reduced the relaxation effect, but did not inhibit it completely. In aortic vascular endothelium 3 µM oxyhemoglobin decreased the relaxation effect by 26% on the average, while 10 µM oxyhemoglobin reduced it by over 52%. The addition of 100 µM L-cysteine produced no significant inhibiting effect. Conclusions: These results suggest that LLNO1 and FONO1 are potent vasodilators. LLNO1 was shown to induce a significant level of relaxation in rabbit corpus cavernosum. The substances tested were shown to activate soluble guanylate cyclase and release intracellular NO.

Modulation of some markers of erectile dysfunction and malonaldehyde levels in isolated rat penile tissue with unripe and ripe plantain peels: identification of the constituents of the plants using HPLC

“…For instance, the up-regulation of phosphodiesterase type 5 (PDE-5) reduces the levels of cGMP in penile tissue, thus impair penile erection (Boswell-Smith et al 2006). In addition, the increased level of cGMP in penile tissues is dependent on NO-induced activation of guanyl cyclase, hence, maximum concentration of NO in the penile tissue is required (Cerqueira et al 2008). In the ED, the increased activity of arginase reduces production of NO, as arginase catalyzes the conversion of arginine to urea and ornithine, thereby reducing arginine levels that could be used for NO production by NO synthase (NOs).…”

Effects of Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), a novel nitric oxide donor, in L-NAME-induced hypertension in rats

“…In the present experiment we attempted to acutely reverse the vasoconstrictor actions of systemic NO blockade with L-NAME by Rut-bpy (NO donor) in anesthetized rats. Studies have demonstrated that Rut-bpy induced maximum relaxation in rat aortic rings 6 , in vitro. In our study the use of Rut-bpy normalized MAP in hypotensive anesthetized rats but was not able to modify the MAP in rats with hypertension induced by L-Name.…”

“…Moreover, it has been demonstrated that metal nitrosyl complexes may induce a decrease in blood pressure levels in hypertensive rats 5 . The novel metallopharmaceutical Rut-bpy (Cis-[Ru(bpy) 2 (SO 3 )(NO)]PF 6 ) is a potent vasodilator capable of releasing intracellular NO and activating guanylate cyclase 6 . Besides producing higher maximum relaxation in aortic rings than sodium nitroprusside at similar molar basis, Rut-bpy is associated with higher levels of NO release without being photosensitive or releasing cyanide 6,7 .…”

“…The novel metallopharmaceutical Rut-bpy (Cis-[Ru(bpy) 2 (SO 3 )(NO)]PF 6 ) is a potent vasodilator capable of releasing intracellular NO and activating guanylate cyclase 6 . Besides producing higher maximum relaxation in aortic rings than sodium nitroprusside at similar molar basis, Rut-bpy is associated with higher levels of NO release without being photosensitive or releasing cyanide 6,7 . Based on those premises, this study was aimed to evaluate the effects of a novel nitrosyl-ruthenium complex -NO donor (Rut-bpy), on L-Name induced hypertension in anesthetized rats.…”

Preconditioning with a Novel Metallopharmaceutical NO Donor in Anesthetized Rats Subjected to Brain Ischemia/Reperfusion

“…Over the past years much attention has been given to nitrosyl-ruthenium complexes and their potential pharmacological use, especially due to their rapid NO release [15] as well as low level of toxicity [16][17][18]. Several ruthenium compounds have been synthesized and purified, but so far none has been tested in studies of experimental brain ischemia and reperfusion.…”